Steven Hsu, M.D. is an Assistant Professor in the Division of Cardiology at Johns Hopkins University. Dr. Hsu seeks an NIH Mentored Patient-Oriented Research Career Development Award in order to obtain the expertise and skills necessary to launch a translational research career focused on human right ventricular (RV) failure. Dr. Hsu has elected to work with primary mentor Dr. David Kass, a pioneer in cardiac physiology and molecular pathobiology, and co-mentor Dr. Paul Hassoun, a thought leader in pulmonary hypertension. Both occupy complementary areas of research expertise, work together seamlessly, and boast long track records of successful funding and training of physician-scientists. A complementary group of collaborators will assist in the research and form an advisory committee as well. Dr. Hsu will leverage their combined mentorship to study the molecular underpinnings of RV sarcomere dysfunction in human scleroderma-associated pulmonary arterial hypertension (PAH). The specific aims of his research proposal are to: (1) identify the alterations in sarcomere proteins troponin I and myosin-binding protein C that underlie the in vivo RV dysfunction of human scleroderma-associated PAH; and (2) determine which RV-directed pharmacotherapies would best restore function in failing RV sarcomeres isolated from these same subjects. Dr. Hsu's career development training objectives during this award period are to develop proficiency in clinical studies, master invasive RV pressure- volume hemodynamics, broaden his translational basic science skillset, and prepare for independent investigator funding. These will enable Dr. Hsu's long-term goal of developing a career dedicated to the translational investigation of human RV heart failure. PAH is a deadly disease resulting from a pathologic increase in pulmonary vascular load. Although pulmonary vasodilator therapies have helped many, the scleroderma-associated PAH subgroup lags far behind its PAH counterparts in terms of functional capacity and survival. Dr. Hsu has first authored two high impact publications showing that failure of RV adaptation in scleroderma-associated PAH is the likely culprit. Scleroderma-associated PAH patients suffer disproportionate RV contractile dysfunction when compared to idiopathic PAH and normal controls, both at the in vivo RV chamber level and the ex vivo RV sarcomere level. Understanding and treating this RV dysfunction would meet a major unmet need in the care of patients with PAH. Preliminary work thus far points towards explanatory molecular alterations in the key sarcomere proteins troponin I and myosin-binding protein C. The proposed research will test the centrality of these two sarcomere proteins to the chamber and cellular RV dysfunction of human scleroderma-associated PAH, while also determining the efficacy of therapeutics directed against the failing RV sarcomere. In doing so, this work seeks to clarify the molecular mechanisms of RV failure in scleroderma-associated PAH, while also innovating the treatment paradigm for the field of PAH.